In recent years, pain management has become an area of increasing focus in the medical profession, partly due to the growing population of elderly, issues surrounding quality of life, and the growing numbers of patients reportedly suffering from pain. Pain is both a sensory and emotional experience, and is generally associated with tissue damage or inflammation. Typically, pain is divided into two general categories—acute pain and chronic pain. Both differ in their etiology, pathophysiology, diagnosis, and most importantly, treatment.
Acute pain is short term, and is typically of a readily identifiable cause. Patients suffering from acute pain typically respond well to medications. In contrast, chronic pain, medically-defined as pain that lasts for 3-6 months or longer, is often not associated with an obvious injury; indeed, patients can suffer from protracted pain that persists for months or years after the initial insult. While acute pain is generally favorably treated with medications, chronic pain is often much more difficult to treat, generally requiring expert care. Reportedly, according to the American Chronic Pain Association, over 86 million Americans suffer from chronic pain, and the management of chronic pain has long been recognized as an unmet clinical need. Most chronic pain is neuropathic in nature (also referred to as neuralgia). Neuropathic pain can, for instance, manifest itself as burning, stabbing, and shock-like sensations.
Unfortunately, neuropathic pain management is at best inconsistent, and often times ineffective. This is in part due to the subjective nature of pain, but also due to poor diagnosis, especially when the chronic pain is not clearly associated with a nerve injury or other insult. Moreover, few, if any, ethical drugs have been prospectively developed for the treatment of chronic pain. Instead, the current medications used to treat chronic pain are “borrowed” from other diseases, most commonly antiepileptic drugs and antidepressants.
Current first-line treatments for chronic pain include opioids, analgesics such as gabapentin, and tricyclic antidepressants. In the instance of opioids, when administered over prolonged periods, undesirable side effects such as drug tolerance, chemical dependency and even physiological addiction can occur. Of treatment regimes currently available for chronic pain, at best, approximately 30% are effective in significantly diminishing the pain, and may lose their efficacy over time. Although numerous pharmacological agents are available for the treatment of neuropathic pain, a definitive therapy has remained elusive.
In instances in which treatment with a single agent proves to be unsuccessful, combination therapy is often then explored as a second line treatment. For example, such combination therapy may employ administration of an opioid agent with an adjuvant analgesic, although the relative doses of each are often subject to prolonged trial and error periods. Oftentimes, triple drug therapy is necessary. Such therapy generally involves a combination of tricyclic antidepressants, anti-convulsants, and a systemic local anesthetic. Patient compliance drops significantly, however, when treatment requires the administration of multiple pharmacologic agents. Recently, researchers reported the use of a combination of morphine and gabapentin in a randomized study for controlling nerve pain (Gilron, I., et al., New Eng. J of Medicine, Vol 352:1281-82, No. 13, Mar. 31, 2005).
Moreover, it is not only important to consider overall pain relief, but also the type of pain relief. For example, chronic pain is typically viewed as allodynia or hyperalgesia. Allodynia is pain sensation from a stimulus that is not normally painful. The allodynia is typically caused by a physical stimulus and thus referred to as tactile or mechanical allodynia. Hyperalgesia is an exaggerated sensation from a stimulus that is normally painful. The hyperalgesia can occur from a variety of stimuli, but commonly, a patient's reaction to hot and cold stimuli is reported. Importantly, physicians often report that the current drugs are most effective at relieving hyperalgesia although most patients complain from allodynia, particularly mechanical allodynia.
In addition to poor and/or inconsistent efficacy, these medications have several other undesirable properties, such as adverse events, duration of action, and complicated dosing and titration regiments.
The most common side-effect of the non-opiate drugs is sedation or somnolence. Based on data from the package inserts for these drugs, as many as 20-30% of patients experience sedation. As mentioned above, the population greatest at risk for chronic pain are elderly. For the elderly, experiencing significant and persistent sedation poses other risks, mainly locomotors function impairment. Such locomotors function impairment can lead to falling and the inability to perform many daily functions such as driving.
The duration of action is also a limitation for most of the leading therapies. This is particularly important as pain, and especially nighttime pain, can lead to depression, insomnia and other factors that impact the patient's overall quality of life. A recent study suggests that patients with chronic pain and concurrent major depression and insomnia report the highest levels of pain-related impairment. This study also found that insomnia in the absence of major depression is also associated with increased pain and distress. (Wilson et al., Clin J Pain 2002 March.-April.; 18(2):77-83.). Therefore, achieving pain relief with a sufficient duration to achieve relief through the night is an important factor for neuropathic pain drugs. Pain-relief drugs such as gabapentin are taken once or more during the night to achieve pain relief—thus disturbing sleep and exacerbating the patient's overall quality of life.
Finally, the dosing or titration of the leading drugs, such as gabapentin, can be complicated. For example, the recommended starting dose for gabapentin in adults with postherpetic neuralgia is a single 300-mg dose on Day 1, 600 mg/day on Day 2 (divided BID), and 900 mg/day on Day 3 (divided TID). If no relief is obtained at these doses, the dose can subsequently be titrated up as needed for pain relief to a daily dose of 1800 mg (divided TID). In clinical studies, efficacy was demonstrated over a range of doses from 1800 mg/day to 3600 mg/day with comparable effects across the dose range.” (Neurontin® Full U.S. Prescribing Information). Other antiepileptic drugs and antidepressants have similar dosing schedules which are similarly complicated, discourage compliance, and increase the chances of incorrect dosing and even overdosing. Further, discontinuing such drugs can also be challenging. For instance, as stated on the Full U.S. Prescribing Information for Neurontin® “ . . . [A]s dose is reduced, discontinued or substituted with an alternative medication, this should be done gradually over a minimum of 1 week.”
Neuropathic pain (NP) is generally thought of as a maladaptive chronic condition in which pain originates from damaged nerves, often yielding pain that is out-of-proportion to the extent of injury. The damage can occur from a physical injury such as trauma or from chemical injury such as chemotherapeutics (e.g., paclitaxol). Neuropathic pain of this type is an important component of a number of syndromes of varying etiologies whose common characteristic is the development of a prolonged and profound pain state. Among these conditions are spinal cord injury, post-herpetic neuralgia, diabetic neuropathy, phantom limb pain, stump/neuroma pain, post-ischemic pain (stroke), fibromyalgia, reflex sympathetic dystrophy (RSD), complex regional pain syndrome (CRPS), cancer-chemotherapeutic induced neuropathic pain, vertebral disk rupture, trigeminal neuralgia, and others.
Recently, however, it has been recognized that neuropathic pain can manifest itself in the absence of an identifiable nerve injury. These indications include AIDS and mirror image pain. The lack of any nerve injury but unmistakable chronic pain has led to increased interest in the role of glial cells in the maintenance of the neuropathic pain state. (Watkins and Maier (2004) Drug Disc. Today: Ther. Strategies 1(1): 83-88). More specifically, recent research has demonstrated that glial enhance the release of neurotransmitters that relay pain information to the spinal cord, and, even more striking, release substances that increase the excitability of pain-responsive neurons in the spinal cord. These substances, called pro-inflammatory cytokines, create and maintain exaggerated or pathological pain responses. Blocking the activation of glia reduces pro-inflammatory cytokines and reverses pathological pain. To date, no therapeutics have been approved that have a putative glial-attenuation mechanism for the treatment of neuropathic pain. Molecules which are glial-attenuators may play an important role in treating neuropathic pain.
The small molecule, ibudilast, (3-isobutyryl-2-isopropylpyrazolo[1,5-a]pyridine), is a non-selective inhibitor of cyclic nucleotide phosphodiesterase (PDE) (Fujimoto, T., et al., J. of Neuroimmunology, 95 (1999) 35-92). Ibudilast also acts as an LTD4 antagonist, an anti-inflammatory, a PAF antagonist, and a vasodilatatory agent (Thompson Current Drug Reports). Ibudilast is thought to exert a neuroprotective role in the central nervous system of mammals, presumably via suppression of the activation of glial cells (Mizuno et al. (2004) Neuropharmacology 46: 404-411). Ibudilast has been widely used in Japan for relieving symptoms associated with ischemic stroke or bronchial asthma. Marketed indications for ibudilast in Japan include its use as a vasodilator, for treating allergy, eye tissue regeneration, ocular disease, and treatment of allergic ophthalmic disease (Thompson Current Drug Reports). In recent clinical trials, its use in the treatment of multiple sclerosis, an inflammatory disease of the central nervous system, has been explored (News.Medical.Net; Pharmaceutical News, 2 Aug. 2005). While the use of ibudilast for a number of varying indications has been reported to date, to the best of the applicants' knowledge, its use in treating neuropathic pain and conditions associated therewith, including allodynia, has heretofore remained largely unexplored.
In light of the above shortcomings in current approaches for treating chronic pain, there exists a need for improved compositions and methods for treating pain, particularly neuropathic pain and its associated symptoms, and more specifically, neuropathic pain associated with certain conditions such as fibromyalgia, among others. Such approaches should ideally overcome one or more of the problems associated with existing methods for treating chronic pain. The present invention meets these needs.